This invention relates to the asymmetric reduction of 1,4-disubstituted-4-imidazolin-2-ones to 1,4-disubstituted imidazolidine-2-ones and conversion of the latter to levamisole.
A novel process for the catalytic asymmetric synthesis of levamisole through reduction of prochiral intermediates is disclosed in U.S. Pat. No. 4,087,611 (1978). Asymmetric reduction is attained through catalysis by homogeneous asymmetric rhodium complexes acting on prochiral 1,4-disubstituted-4-imidazolin-2-ones. The maximum enantioselectivity disclosed was 33% enantiomeric excess achieved with a catalyst system derived from (+) DIOP and [Rh(COD)Cl].sub.2 acting on 1-(2-methoxyethyl)-3-acetyl-4-phenyl-4-imidazolin-2-one. The reduced product was converted to levamisole with retention of chirality.
Reduction of various substituted prochiral olefins using homogeneous asymmetric complexes of rhodium (I) salts as catalysts is a field that has been extensively examined in recent years. A review of the state of this art by H. B. Kagan has recently appeared in Pure and Applied Chem., 43, 401 (1976) which is incorporated herein by reference. For specified prochiral substrates the degree of enantioselectivity achieved in reduction has been found to be strongly influenced by the choice of the asymmetric tertiary phosphine derivative employed as a ligand in the catalyst complex. Different prochiral substrates have been found to require different asymmetric catalyst ligands for maximum enantioselectivity in catalytic reduction.
Specifically the use of rhodium complexes of bistertiary phosphines as catalysts is disclosed as follows:
U.S. Pat. No. 3,949,000 discloses asymmetric diphosphines which, when reacted with a rhodium (I) halogen salt, produces a rhodium complex. The rhodium complex is then used as a catalyst for the hydrogenation of precursors of amino acids.
Canadian Pat. No. 977,373 discloses rhodium coordination complexes, containing phosphine and at least one halogen ion, wherein the optical activity of the complex resides in the phosphine ligand. These complexes are useful as catalysts in the asymmetric hydrogenation of .alpha.-amino acids.
ASYMMETRIC CATALYSIS BY CHIRAL RHODIUM COMPLEXES IN HYDROGENATION AND HYDROSILYLATION REACTIONS, H. B. Kagan, "Pure and Applied Chemistry," 43, p. 401 (1976) discloses asymmetric catalysis of optically active enamides and precursers of .alpha.-amino acids using a chiral diphosphine rhodium complex as a homogeneous catalyst.
All of the above references are incorporated herein by reference.
Also, U.S. Pat. No. 4,087,611 (1978) [application Ser. No. 739,923 filed Nov. 8, 1976 which is a Continuation-in-part of U.S. patent application Ser. No. 680,302, filed Apr. 26, 1976, now abandoned,] discloses a process of using a chiral rhodium diphosphine catalyst to directly manufacture an optically active levamisole. See, e.g., U.S. Pat. No. 4,087,611 [Application 739,923, page 9] columns 5, 6, 7 and 8.
The greater enantioselectivity that can be achieved through catalytic asymmetric reduction, the greater the yield of levamisole or other useful enantiomer obtained.
There has been no previous evidence that the selection of the anion of the rhodium (I) complex salt used for homogeneous asymmetric catalytic reduction can have a significant effect on the degree of enantioselectivity obtained in the reduced substrate. In fact, for other substrate systems found in the prior art, it has been noted that the degree of enantioselectivity is independent of the anion. See, Knowles, J.A.C.S., 99, 5946 (1977); Kagan, supra, page 411. Since rhodium complexes with different anions are readily prepared by known methods, see, e.g., I. Chatt and L. M. Vananzi, J. Chem. Soc. 4735(1957), improvements in enantioselectivity obtained by such modification could readily be made practical.